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J Am Chem Soc. 2019 Jul 10;141(27):10770-10776. doi: 10.1021/jacs.9b03663. Epub 2019 Jun 28.

A Transient and Flexible Cation-π Interaction Promotes Hydrolysis of Nucleic Acids in DNA and RNA Nucleases.

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Laboratory of Molecular Modeling and Drug Discovery , Istituto Italiano di Tecnologia , Via Morego 30 , 16163 , Genoa , Italy.
European Molecular Biology Laboratory (EMBL) Grenoble , 71 Avenue des Martyrs , Grenoble 38042 , France.


Metal-dependent DNA and RNA nucleases are enzymes that cleave nucleic acids with great efficiency and precision. These enzyme-mediated hydrolytic reactions are fundamental for the replication, repair, and storage of genetic information within the cell. Here, extensive classical and quantum-based free-energy molecular simulations show that a cation-π interaction is transiently formed in situ at the metal core of Bacteriophage-λ Exonuclease (Exo-λ), during catalysis. This noncovalent interaction (Lys131-Tyr154) triggers nucleophile activation for nucleotide excision. Then, our simulations also show the oscillatory dynamics and swinging of the newly formed cation-π dyad, whose conformational change may favor proton release from the cationic Lys131 to the bulk solution, thus restoring the precatalytic protonation state in Exo-λ. Altogether, we report on the novel mechanistic character of cation-π interactions for catalysis. Structural and bioinformatic analyses support that flexible orientation and transient formation of mobile cation-π interactions may represent a common catalytic strategy to promote nucleic acid hydrolysis in DNA and RNA nucleases.


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